Releasable polymeric conjugates based on aliphatic biodegradable linkers

• US 20040037802A1
• Filed: 08/13/2002
• Published: 02/26/2004
• Est. Priority Date: 08/13/2002
• Status: Active Grant

• Current Assignee: Belrose Pharma, Inc.
• Original Assignee: Enzon Pharmaceuticals Inc. (Icahn Associates Holding LLC)
• Inventors: Zhao, Hong, Greenwald, Richard B., Pendri, Annapurna
• Granted Patent: US 7,122,189 B2
• Time in Patent Office: Days
• US Class Current: 424/78.26
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: C07C 271/16 to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
• CPC Class Codes: C07C 271/20 to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
• CPC Class Codes: C07C 271/22 to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 317/28 with sulfone or sulfoxide groups bound to acyclic carbon atoms of the carbon skeleton
• CPC Class Codes: C07D 207/452 with hydrocarbon radicals, substituted by hetero atoms, directly attached to the ring nitrogen atom
• CPC Class Codes: C07D 277/16 Sulfur atoms
• CPC Class Codes: C07D 333/34 Sulfur atoms
• CPC Class Codes: C07K 14/43595 from coelenteratae, e.g. medusae

Abstract

Activated polymeric bicine derivatives such as

as well as conjugates made therewith are disclosed. Methods of making and using the bicine derivatives are also disclosed.

Claims

1. A compound comprising the Formula (I):

2. The compound of claim 1, wherein R₃-R₁₀ and R_24-25 are each hydrogen.

3. The compound of claim 1, wherein a, b, c, d, m, n, o and p are each 1 and e is 0 or 1.

4. The compound of claim 1, wherein R₁ comprises a polyalkylene oxide.

5. The compound of claim 1, wherein R₂ comprises a polyalkylene oxide.

6. The compound of claim 1, wherein R₁ comprises a polyethylene glycol.

7. The compound of claim 1 wherein R₂ comprises a polyethylene glycol.

8. The compound of claim 1 wherein R₁ or R₂ further include a capping group J, selected from the group consisting of OH, NH₂, SH, CO₂H, C_1-6 alkyl moieties,

9. A compound of claim 8, selected from the group consisting of:

10. The compound of claim 1, wherein R₁ is selected from the group consisting of:

J—

O—

(CH₂CH₂O)_x—

J—

O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,J—

O—

(CH₂CH₂O)_x—

CH₂CH₂ NR₁₂—

,J—

O—

(CH₂CH₂O)_x—

CH₂CH₂ SH—

,—

OC(O)CH₂—

O—

(CH₂CH₂O)_X—

CH₂C(O)—

O—

,—

NR₁₂CH₂CH₂—

O—

(CH₂CH₂O)_X—

CH₂CH₂NR₁₂— and

—

SHCH₂CH₂—

O—

(CH₂CH₂O)_X—

CH₂CH₂SH—

.

wherein;

x is the degree of polymerization;

R₁₂ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_3-8 substituted cycloalkyls, aryls, substituted aryls, aralkyls, C_1-6 heteroalkyls, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy; and

J is a capping group.

11. The compound of claim 1, wherein R_1-2 are individually selected from the group consisting of:

CH₃—

O—

(CH₂CH₂O)_x—

, CH₃—

O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,CH₃—

O—

(CH₂CH₂O)_x—

CH₂CH₂ NH— and

CH₃—

O—

(CH₂CH₂O)_x—

CH₂CH₂ SH—

wherein x is the degree of polymerization.

12. The compound of claim 10, wherein R₂ is selected from the group consisting of:

J—

O—

(CH₂CH₂O)_x—

J—

O—

(CH₂CH₂O)_x—

CH₂C(O)—

O—

,J—

O—

(CH₂CH₂O)_x—

CH₂CH₂ NR₁₃—

,J—

O—

(CH₂CH₂O)_x—

CH₂CH₂ SH—

,—

OC(O)CH₂—

O—

(CH₂CH₂O)_X—

CH₂C(O)—

O—

,—

NR₁₃CH₂CH₂—

O—

(CH₂CH₂O)_X—

CH₂CH₂NR₁₃— and

—

SHCH₂CH₂—

O—

(CH₂CH₂O)<sub>X—

CH2</sub>CH₂SH—

,

wherein;

x is the degree of polymerization;

R₁₃ is selected from the group consisting of hydrogen, C_1-6 alkyls, C_3-19 branched alkyls, C_3-8 cycloalkyls, C_1-6 substituted alkyls, C_3-8 substituted cycloalkyls, aryls substituted aryls, aralkyls, C_1-6 heteroalkyls, substituted C_1-6 heteroalkyls, C_1-6 alkoxy, phenoxy and C_1-6 heteroalkoxy and J is a capping group.

13. The compound of claim 1, wherein R₁ and R₂ each comprise a polymer residue of the formula —

O—

(CH₂CH₂O)_x.

14. The compound of claim 13, wherein R₁ and R₂ each have a weight average molecular weight of from about 2,000 Da to about 25,000 Da.

15. The compound of claim 1 wherein L₁ is selected from the group consisting of:

—

NH(CH₂CH₂O)₂CH₂C(O)—

—

NH(CH₂)₃OC(O)—

—

(CH₂)_tC(O)—

,—

C(O)NH(CH₂)_tC(O)—

,—

NH(CH₂)_tC(O)—

,—

NR₁₉(CH₂)_t(CH₂CH₂O)_qNHC(O)—

—

(CH₂CH₂O)_tNHC(O)—

—

O(CR₁₄R₁₅)_tNHC(O)—

—

NR₁₉(CR₁₄R₁₅)_qC(O)NH(CR₁₆R₁₇)_tC(O)—

—

O(CH₂)_tOC(O)—

—

NR₁₉(CR₁₄R₁₅)_tC(O)—

—

NR₁₉(CH₂)_t(CH₂CH₂O)_qNHC(O)—

—

NR₁₉(CH₂CH₂O)_t—

OC(O)—

—

O(CR₁₄R₁₅)_tNHC(O)—

—

O(CR₁₄R₁₅)_tOC(O)—

—

(CH₂CH₂O)_tNHC(O)—

16. The compound of claim 1 wherein L₂ is selected from the group consisting of:

—

NH(CH₂CH₂O)₂CH₂C(O)—

—

NH(CH₂)₃OC(O)—

—

(CH₂)_vC(O)—

,—

C(O)(CH₂)_vNHC(O)—

,—

NH(CH₂)_vC(O)—

,—

NR₂₅(CH₂)_v(CH₂CH₂O)_wNHC(O)—

—

(CH₂CH₂O)_vNHC(O)—

,—

O(CR₂₀R₂₁)_vNHC(O)—

,—

NR₂₅(CR₂₀R₂₁)_w(O)CNH(CR₂₂C₂₃)_vC(O)—

—

O(CH₂)_vOC(O)—

—

NR₂₅(CR₂₀R₂₁)_vC(O)—

—

NR₂₅(CH₂)_v(CH₂CH₂O)_wNHC(O)—

—

NR₂₅(CH₂CH₂O)_v—

O—

C(O)—

O(CR₂₀R₂₁)_vNHC(O)—

—

O(CR₂₀R₂₁)_vOC(O)—

—

(CH₂CH₂O)_vNHC(O)—

17. A compound of claim 1, comprising the formula:

18. A compound of claim 1, selected from the group consisting of:

19. The compound of claim 1, wherein A₁ is a leaving group selected from the group consisting of

20. The compound of claim 1, wherein A is selected from the group consisting of maleimidyl, vinyl, residues of sulfone, hydroxy, amino, carboxy, mercapto, hydrazide, carbazate functional groups.

21. The compound of claim 20, wherein A is:

22. The compound of claim 1, wherein said terminal branching group comprises the formula:

23. A compound of claim 22, comprising the structure:

24. A compound of claim 22, comprising the structure:

25. A compound of claim 1, selected from the group consisting of

26. A compound of claim 1, selected from the group consisting of

29. A method of treatment, comprising administering to a mammal in need thereof, an effective amount of a compound of claim 1, wherein A is a residue of an amine-containing biologically active agent.

27. A method of preparing a polymer conjugate, comprising reacting a compound of the formula:

28. A method of preparing a bicine-based polymer transport system, comprising

a) synthesizing an acid protected bicine;

b) attaching a blocked bifunctional spacer to each hydroxyl of the acid protected bicine;

c) deprotecting the resultant intermediate and reacting it with an activated polymer under basic coupling conditions; and

d) deprotecting and activating the blocked acid of said acid protected bicine under coupling conditions.